Hemostasis of wound having high pressure blood flow

ABSTRACT

Compositions comprising clay minerals and methods for their use in promoting hemostasis are provided. The compositions comprise clay minerals such as bentonite, and facilitate blood clotting when applied to a hemorrhaging wound. Electrospun or electrosprayed materials (e.g. bandages, micron beads, etc.) which include clay minerals, and methods for the treatment of acute hemorrhage, are also provided.

BACKGROUND OF THE INVENTION Field of the Invention

The invention generally relates to compositions and methods forpromoting hemostasis. In particular, the invention provides compositionscomprising clay minerals, which, when applied to a bleeding area,function to 1) absorb liquid and 2) promote blood clotting.

Background of the Invention

Hemorrhagic events, from the minor to the life threatening, result froma wide variety of circumstances and occur in a wide variety of settings.The conditions which result in hemorrhage may be relatively predictable,such as those associated with medical procedures. Alternatively,hemorrhagic events may result from unpredictable circumstances, such asa breach of the skin or an internal organ in an accident. Such acutetraumatic wounds occur in an almost infinite number of patterns anddegrees, making the use of simple compression or application of a singletype of bandage, impractical if not impossible, especially in the mostsevere circumstances. For example, a traumatic wound to the groin cannotbe readily controlled either by simple direct pressure or by the use ofa simple flat bandage.

Attempts have been made which partially address the treatment ofhemostasis, and/or the need for flexibility in wound dressings:

-   1) Hemcon's Chitosan Bandage (see the website located at hemcon.com)    is a gauze bandage impregnated with chitosan. Chitosan, a fiber    derived from chitin in shellfish, is a nondigestible    aminopolysaccharide. Chitosan is synthesized by removing acetyl    groups from chitin, through a process called deacetylation. Chitosan    is known to have significant coagulant properties which are believed    to be based on its cationic (positive charge) properties. However,    its mucoadhesive properties may also be responsible. In models of    life threatening hemorrhage (J Trauma 2005; 59:865-875 and J Trauma    2004; 56:974-983), the ability of the bandage to improve survival    has been limited. In one study, use of the bandage had a 100%    failure rate (isolated arterial injury). In a second study (combined    arterial and venous hemorrhage at low blood pressures) the bandage    resulted in a 28% mortality rate. It was noted that there was a    bandage-to-bandage variability in performance and ability of the    bandage to adhere to the wound. This bandage is available in only    one size and formulation. The ability to produce a powder or    granular form of chitosan similar to that of QuickClot or the    bentonite clay described in this application is likely to be    limited. Powdered chitosan does not mix well with blood.-   2) The Fibrin Sealant Dressing (FSD) is the result of a    collaborative effort between the U.S. Army and the American Red    Cross. It is made from fibrin, thrombin, and factor XIII purified    from human donated blood and plasma. It is thus a biologic which has    a potential for disease transmission even though this risk is small.    The FSD controls hemorrhage by promoting natural clot formation at    the site of injury since it provides concentrated coagulation    factors at the site of injury. However, it is a biologic and the    manufacture of such bandages is extremely labor-intensive, and their    cost may prohibit routine use in most circumstances (estimated cost    between $500 and $1000). The dressings are fragile and tend to break    apart if not carefully handled. In a study performed by the U.S.    Army (J Trauma 2005; 59:865-875) utilizing a model of severe    arterial bleeding, the FSD bandage significantly improved survival    when compared with the Army Field dressing, QuickClot and the HemCon    bandage. The product comes only in bandage form.-   3) The Rapid Deployable Hemostat (RDH) is a bandage made by Marine    Polymer Technologies and incorporates a derivative from sea algae to    promote hemostasis. However, in a study by Alam and colleagues    (Alam, et al. J Trauma 2003; 54:1077-1082), which explored the    ability of many commercial products to stop severe bleeding and to    increase survival, use of the RDH resulted in lower survival rates    than a simple standard bandage. This would indicate that the current    components of the RDH are not suitable for use in life threatening    hemorrhage. Furthermore, to our knowledge, this product's only    available form is one of a bandage. The cost of this product may be    expensive and is currently estimated to be approximately $300 per    unit.-   4) U.S. Pat. No. 4,748,978 (to Kamp) discloses a therapeutic    dressing that includes a flexible permeable support and a mixture of    mineral components, including bentonite, kaolinite and illite or    attapulgite, and may include anti-fungal (or other) agents as well.    The dressing is reported to be designed to be flexible and to be    able to be made or cut to any desired size. It is reported to be    intended primarily to treat burns, but can also be used for the    treatment of ulcers. However, the dressing is not described as    suitable for the treatment of hemorrhage, and no data from Kamp is    available to support its use for this indictaion.-   5) U.S. Pat. No. 4,822,349 (to Hursey et al.) describes a    non-bandage material used to treat bleeding. The material is sold by    Z-Medica as “Quick-Clot” (see the website located at z-medica.com)    and is a granular form of zeolite, an aluminum silicate mineral.    During use, it is poured into a wound. In addition to absorbing    water from hemorrhaged blood and concentrating hemostatic factors in    the blood at the site of injury, its mechanism of action appears to    involve chemical cautery. An intense exothermic reaction is produced    upon contact with liquid (e.g. blood), and is likely responsible for    stoppage of blood flow by cauterization. While use of this material    may be preferable to bleeding to death, the attendant burning of    tissue at and near the wound (and possible burn injury of medial    personnel who are administering the material) is clearly a severe    disadvantage. This side effect also reduces the ability of the    material to be used for internal hemorrhage. While the manufacturer    indicates that the main mechanism of action is the superaborbant    nature of zeolite which absorbs water out of blood to concentrate    clotting factors, the patent (U.S. Pat. No. 4,822,349 (to Hursey et    al.) indicates that its action lies mainly through the exothermic    reaction it creates. Studies by Alam and colleagues (J Trauma 2004;    56:974-983) clearly demonstrate that the ability of this product to    stop hemorrhage is quickly lost when it is partially hydrated in    attempts to reduce the exothermic reaction and the resulting    temperature it produces in tissues. When the granules are placed in    a bag similar to a tea bag to facilitate removal, its ability to    stop bleeding is significantly limited. In addition, to our    knowledge this product has not been made into a bandage and even if    it were it would likely still produce a significant exothermic    reaction upon contact with blood.-   6) A product made by TraumaDex (see the website located at    traumadex.com) is also a non-bandage. In this case, the product is a    powder consisting of microporous beads which absorb water and which    contain concentrated clotting factors. During use, the material is    poured or squirted into the wound. However, when studied by Alam and    colleagues (J Trauma 2003; 54:1077-1082) in a model of severe    hemorrhagic shock, TraumaDex performed no better than a standard    field dressing, thus offering no advantage and certainly more    expense. Alam and colleagues studied this product again (J Trauma    2004; 56:974-983) and demonstrated its performance to be suboptimal    compared to QuickClot and the Hemcon bandage. In this study, it    performed only slightly better than a standard dressing. Also to our    knowledge, this product has not been made into a bandage and even if    it were it would probably lack efficacy in stopping severe bleeding.

A “one size fits all” approach to the treatment of hemorrhage clearlydoes not and cannot work, and the prior art has thus far failed toprovide compositions and methods to treat hemorrhage that areinexpensive, efficacious, highly adaptable, easy to use, and lacking inserious side effects.

SUMMARY OF THE INVENTION

The invention is based on the surprising discovery that formulationscomprising certain relatively inexpensive and readily available clayminerals are highly effective in promoting blood clotting and stanchingthe flow of blood when applied to a hemorrhaging wound. Application ofthe material does not cause an exothermic reaction upon contact with theliquid components of blood. Thus, there is no danger of possible tissuedamage by burning. The compositions of the invention can thus be usedsafely in any situation that requires the treatment of hemorrhage,including internal bleeding. An exemplary type of such a clay mineral isbentonite.

The present invention provides compositions comprising clay minerals andmethods for their use for effectively treating and controllinghemorrhage in a large number of variable scenarios. The compositions arerelatively inexpensive to manufacture, highly effective, highlyadaptable and easy to use, and cause no serious side effects. The claymineral compositions provided herein can be used in a flexible manner totreat hemorrhage under a wide-ranging variety of circumstances.

It is an object of this invention to provide a method of promotinghemostasis in a hemorrhaging wound. The method comprises the step ofapplying a composition comprising one or more clay minerals to thehemorrhaging wound. The clay minerals are applied in a quantitysufficient to promote one or both of the following: i) hemostasis andii) formation of a cast (e.g. a hardened plug) comprising the one ormore clay minerals and blood from the hemorrhaging wound. The one ormore clay minerals may be selected from the group consisting ofkaolin-serpentine type clays, illite type clays and smectite type clays.In one embodiment, the one or more clay minerals is bentonite. The oneor more clay minerals may be in a form such as, for example, granules,powder, micron beads, liquid, paste, gel, impregnated in a bandage, andelectospun into a bandage. The composition may further comprise one ormore substances such as, for example, superabsorbent polymers, chitosan,fibrin(ogen), thrombin, calcium, vasoactive catecholamines, vasoactivepeptides, electrostatic agents, antimicrobial agents, anesthetic agents,fluorescent agents, and quick dissolve carrier polymers such as dextranand polyethylene glycol (PEG). The hemorrhaging wound that is treatedmay be an external wound or an internal wound. The wounds may be theresult of accidental or intentional trauma or by tissue breakdown fromdisease. Examples of tissue breakdown leading to severe bleeding includegastrointestinal bleeding as a result of ulcers, among others.Intentional trauma includes trauma that occurs as a result of surgicalmanipulation of tissue, due to, for example, repair of the tissue,repair or removal of adjacent tissue, the need to surgically insert orremove medical devices, etc.

The invention further provides an electrospun fiber comprising one ormore clay minerals. The one or more clay minerals may be, for example,kaolin-serpentine type clays, illite type clays and smectite type clays.In one embodiment, the one or more clay minerals is bentonite. Theelectrospun fiber may further comprising one or more substances such as,for example, gelatin, a super-absorbent polymer, chitosan, fibrin(ogen),thrombin, calcium, vasoactive catecholamines, vasoactive peptides,antimicrobial agents, anesthetic agents and fluorescent agents. Theelectrospun fiber may be crosslinked.

The invention also provides a method of making an electrospun fiber,comprising the steps of 1) forming a composition comprising one or moreclay minerals and a solvent, and 2) electrospinning the composition toform the electrospun fiber. In one embodiment, the solvent is2,2,2-trifluoroethanol. The composition to form the electrospun fibermay further comprise one or more substances such as, for example,gelatin, a super-absorbent polymer, chitosan, fibrin(ogen), thrombin,calcium, vasoactive catecholamines and vasoactive peptides. The methodmay further comprise the step of crosslinking the electrospun fiber.

In yet another embodiment, the invention provides a bandage comprised ofelectrospun fibers, wherein the electrospun fibers comprise one or moreclay minerals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Schematic representation of exemplary electrospinning apparatus.

FIG. 2: Product obtained from electrospinning of gelatin alone (200mg/mL of 2,2,2-trifluoroethanol, TFE).

FIG. 3: Product obtained from electrospinning of gelatin (200 mg/mL TFE)with pulverized bentonite clay (300 mg/mL TFE).

FIG. 4: Product obtained from electrospinning of gelatin (200 mg/mLTFE), pulverized bentonite clay (300 mg/mL) and a blend of crosslinkedsodium salt of polyacrylic acid with particle size distribution lessthan 300 microns (LiquiBlock 144: Emerging Technologies Inc. GreensboroN.C.) (100 mg/mL TFE).

FIG. 5: Product obtained from electrospinning of gelatin (200 mg/mL TFE)and Bentonite Clay Powder (300 mg/mL TFE).

FIG. 6: Product obtained from electrospinning of gelatin (200 mg/mLTFE), Bentonite Clay Powder (300 mg/mL TFE) and sodium salt ofpolyacrylic acid with particle size distribution less than 300 microns(100 mg/mL TFE).

FIG. 7. A-C. Coagulation studies with bentonite. A, effect of bentoniteon platelet function; B, effect of bentonite of clot structure; C,Thromboelastograph (TEG®) data with varying concentrations of bentonite.

FIG. 8A-C. Coagulation studies with bentonite compared to fibrinogen. A,Effects of bentonite and fibrinogen on platelet function; B, effects ofelectrospun materials on clot structure; C, Thromboelastograph (TEG®)data.

FIGS. 9A and B. Comparison of bentonite, gelatin and zeolite. A, effectof 10 mg/mL of these agents on platelet function; B, effect of 10 mg/mLof these agents on clot structure.

FIG. 10A-B. Comparison of bentonite, gelatin and zeolite. A, effect of50 mg/mL of these agents on platelet function; B, effect of 50 mg/mL ofthese agents on clot structure.

FIG. 11A-E. Thromboelastograph (TEG®) data for bentonite, gelatin andzeolite. A, 10 gm/mL; B, 50 mg/mL; C, 75 mg/mL; D, zeolite at 10, 50 and75 mg/mL; E, bentonite at 10, 50 and 75 mg/mL.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention provides compositions comprising clay minerals andrelated materials, and methods for their use in treating and controllinghemorrhage, i.e. in promoting hemostasis. By “hemorrhage” or “acutehemorrhage” we mean the loss of blood from one or more anatomical sitesof a patient that, if left untreated, would jeopardize the health of thepatient. Hemorrhage typically results from rupture of one or more bloodvessels, which may occur accidentally (e.g. as in accidental wounds) orpurposefully (e.g. during surgical procedures). The active control ofhemorrhage is referred to as “hemostasis”. The promotion of hemostasisinvolves, for example: slowing or stanching the flow of blood; andenhancing, facilitating or causing the blood to clot, particularly atthe site of a wound.

The word “clay” has no standard definition among the various fields towhich it applies (e.g. geology, minerology, etc.). However, thoseskilled in the relevant arts generally recognize that clay is a veryfine grained inorganic mineral material that is plastic when wet, andthat hardens when dried. Most clays, having been formed by theweathering of silicate minerals in igneous rocks, are included in thesilicate class of minerals and the subclass phyllosilicates.Phyllosilicates are formed from continuous sheets of tetrahedra, thebasic unit of which is (Si₂O₅)⁻². Phyllosilicates in turn contain theclay group, comprised of hydrous layered silicates in which Alsubstitutes for some of the Si, the basic unit being (AlSi₃O₁₀)⁻⁵. Clayminerals generally exhibit high aqueous absorption capacities. However,unlike some silicate minerals (such as zeolite of the tectosilicatesubclass), phyllosilicates and clays do not react exothermically in thepresence of liquid.

The present invention is based in part on the surprising discovery thatclay minerals and related materials are highly effective in causingrapid blood clotting. Thus, they are excellent candidates for use incompositions and methods to treat hemorrhage. In addition, clay mineralsare readily available and relatively inexpensive, and they are amenableto manipulation into a variety of forms.

By “clay minerals and related materials” we mean naturally occurring orsynthetic inorganic material that exhibits the properties of clayminerals, e.g. the material is mineral in nature; dry forms of thematerial exhibit high aqueous absorption capacities; the materialexhibits plasticity (ability to be molded) when particulate forms of thematerial are mixed with aqueous-based liquid; the material is devoid ofexothermic activity when mixed with aqueous-based liquid; the materialcauses rapid clotting of blood. In preferred embodiments of theinvention, the materials utilized in the practice of the invention areclay minerals such as various forms of kaolinite-serpentine type clays,illite type clays and smectite type clays, etc. or combinations thereof.Materials related to clay minerals which may be used in the practice ofthe invention include but are not limited to volcanic ash (a precursorof mineral clay) and other similar natural and synthetic minerals,compounds and clays.

In one embodiment of the invention, the materials are naturallyoccurring hydrated aluminum silicates referred to as bentonites.Bentonite is comprised of a three layer structure with alumina sheetssandwiched between tetrahedral silica units. Simplified formulas forbentonite are: 1) (OH)₂Al₂Si₄O₁₀; and 2) Al₂O₃.4SiO₂.H₂O. Bentonite is aplastic clay generated from the alteration of volcanic ash, and consistspredominately of smectite minerals, especially montmorillonite.Bentonite synonyms include sodium bentonite, calcium montmorillonite,saponite, montmorillonite sodium, montmorillonite calcium, taylorite,aluminum silicate, fuller's earth, and others. There are three majortypes of bentonite: 1) natural calcium bentonite; 2) natural sodiumbentonite; and 3) sodium activated bentonite. In general, sodiumactivated bentonites have superior swelling and gelling propertiescompared to calcium bentonites. The term “bentonite” as used herein inintended to encompass all synonyms and all types of bentonite, unlessotherwise specified.

Commercial, food, and pharmaceutical grade bentonites are readilyavailable, as are a variety of particle or mesh sizes. Current uses ofbentonite include the following: foundry sand, paints, thickening,suspending, sealing, bonding, binding, emulsification, absorption,moisture retention, carriers, water proofing, water filtering anddetoxification, beverage, food, and cosmetics. Because of it absorptiveand clumping ability, one of the most common uses of bentonite clay hasbeen for cat litter.

Bentonite clay in various forms and mixtures is also promoted as adetoxifying agent when orally consumed. It appears to have the abilityto absorb potential toxins through its structure and ionic charges. Ithas been postulated that it may also have anti-proteolytic effects.These properties would also contribute to the treatment of acute andchronic wounds to promote healing, prevent infection, and to controlpain. Furthermore, because bentonite clay is known to be consumedwithout ill effects, its use to treat gastrointestinal or other internalhemorrhaging would be expected to be safe.

In another embodiment of the invention, the mineral clay that is used iskaolin (anhydrous aluminum silicate). One known use of kaolin is in thecommon coagulation test called the “activated partial thromboplastintime” which is a measure of the activity of the intrinsic clottingsystem. The activator for this test is kaolin.

Clay minerals have been found to have a remarkable and unexpectedability to cause blood to clot. Even heparinized blood will clot intheir presence. Without being bound by theory, it is noted that thedistribution of cations and anions in this type of material may causefavorable hemostasis, since cationic species are known to cause red cellaggregation and hence clotting, perhaps through a cation exchangemechanism. The negative charge of the clay may activate the intrinsicclotting system because a negative charge is known to possess thisability. The structural composition of the mineral along with its ionicdistribution of charges also provides impressive absorptive properties.In terms of hemorrhage, this would provide for rapid absorption of bloodcomponents which may concentrate intrinsic clotting factors, includingplatelets, at the site of injury.

The clay mineral compositions utilized in the present invention mayinclude one or more clay minerals, i.e. a mixture of clays may beutilized. Those of skill in the art will recognize that such mixturesmay occur naturally, in that deposits of mineral clays may or may not beof purely one type. Alternatively, the mixtures may be formedpurposefully during production of the compositions.

The clay mineral compositions utilized in the practice of the presentinvention may be formulated in a variety of ways. Examples include butare not limited to liquids, foams, powders, granules, gels, hydrogels,sprays, incorporation into bandages, etc. Depending on the application,such formulations may vary, for example, in viscosity, particle size,etc. In addition, a variety of other compounds or materials may be addedto the clay minerals, examples of which include antimicrobial (e.g.anti-biotic, anti-fungal, and/or anti-viral) agents, electrostaticagents (e.g. dendrimers in which the charge density is varied or similarcompounds), preservatives, various carriers which modulate viscosity(e.g. for a spray formulation), various colorants, and variousmedicaments which promote wound healing. Other appropriate hemostatic orabsorptive agents may also be added. These include but are not limitedto chitosan and its derivatives, fibrinogen and its derivatives(represented herein as fibrin(ogen), e.g. fibrin, which is a cleavageproduct of fibrinogen, or super-absorbent polymers of many types,cellulose of many types, other cations such as calcium, silver, andsodium or anions, other ion exchange resins, and other synthetic ornatural absorbent entities such as super-absorbent polymers with andwithout ionic or charge properties. In some embodiments of theinvention, cations of one type in the clay may be substituted withcations of another type (e.g. silver cations), the latter having a morefavorable clotting activity.

In addition, the clay mineral may have added to it vasoactive or otheragents which promote vasoconstriction and hemostasis. Such agents mightinclude catecholamines or vasoactive peptides. This may be especiallyhelpful in its dry form so that when blood is absorbed, the additiveagents become activated and are leached into the tissues to exert theireffects. In addition, antibiotics and other agents which preventinfection (any bacteriocidal or bacteriostatic agent or compound) andanesthetics/analgesics may be added to enhance healing by preventinginfection and reducing pain. In addition, fluorescent agents orcomponents could be added to help during surgical removal of some formsof the mineral to ensure minimal retention of the mineral afterdefinitive control of hemorrhage is obtained. These could be viewedduring application of light for example from a Wood's lamp. In short,any suitable material may be added, so long as the mineral claycomposition is still able to cause blood clotting and promotehemostasis.

The formulations of the present invention may be administered to a siteof bleeding by any of a variety of means that are well known to those ofskill in the art. Examples include but are not limited to internally(e.g. by ingestion of a liquid or tablet form), directly to a wound,(e.g. by shaking powdered or granulated forms of the material directlyinto or onto a site of hemorrhage), by placing a material such as abandage that is impregnated with the material into or onto a wound, byspraying it into or onto the wound, or otherwise coating the wound withthe material. Bandages may also be of a type that, with application ofpressure, bend and so conform to the shape of the wound site. Partiallyhydrated forms resembling mortar or other semisolid-semiliquid forms,etc. may be used to fill certain types of wounds. For intra-abdominalbleeding, we envision puncture of the peritoneum with a trocar followedby administration of clay mineral agents of various suitableformulations. Formulations may thus be in many forms such as bandages ofvarying shapes, sizes and degrees of flexibility and/or rigidity; gels;liquids; pastes; slurries; granules; powders; and other forms. The clayminerals can be incorporated into special carriers such as liposomes orother vehicles to assist in their delivery either topically,gastrointestinally, intracavitary, or even intravascularly. In addition,combinations of these forms may also be used, for example, a bandagethat combines a flexible, sponge-like or gel material that is placeddirectly onto a wound, and that has an outer protective backing of asomewhat rigid material that is easy to handle and manipulate, the outerlayer providing mechanical protection to the wound after application.Both the inner and outer materials may contain clay minerals. Any meansof administration may be used, so long as the mineral clay makessufficient contact with the site of hemorrhage to promote hemostasis.

In yet another embodiment of the invention, the mineral clay isincorporated into a fiber-like material for use in bandages using thetechnique of electrospinning. Electrospinning involves drawing asolution, usually liquid polymers dissolved in solvents, through a smallnozzle within a high-energy electric field. The charged solution forms aliquid jet as it moves out the nozzle toward a grounded target, such asa metal plate or rod. During liquid jet travel, the solvent evaporates,forming a solid fiber that collects on the target as a non-woven“fabric” or mat/scaffolding. The main advantages of this polymer fiberprocessing technique are that it is fairly simple, scalable, efficient,and rapid (requires only minutes to create complex structures). Anexemplary electrospinning system is illustrated in FIG. 1. Thisconfiguration permits the creation of scaffolds with micro- tonano-scale fibers. Additionally, random or highly aligned (high mandrelrotational speeds with fibers aligned circumferentially) fiberstructures can be fabricated. The major factor in controlling fiberdiameter is the polymer solution concentration. A linear relationshipexists between polymer concentration and polymer fiber diametersproduced, with a lower concentration resulting in finer fiber diameters.

In the case of electrospinning clay minerals, the mix of materials thatis electrospun will, in general include, in addition to the mineralclay, a carrier polymer (natural and/or synthetic) for the insolubleclay, a solvent to dissolve the carrier polymer(s), and/or an absorbentpolymer. The addition of an absorbent polymer facilitates exposure ofthe blood to the entire structure of the electrospun fibrous material(e.g. bandage) and not just the surface of the material that is incontact with the blood. Possible additives to electrospun materialinclude those which can be added to other clay mineral compositions andmaterials, as described above.

In an alternative embodiment, beads in the micron size range may beformed from compositions of the present invention. Those of skill in theart will recognize that by lowering polymer concentrations, a solutionresults which may be electrosprayed (rather than electrospun), and theproduct that results is in the shape of micron-sized balls or beads.Such beads may be used in the practice of the invention in much the sameway as pulverized bentonite is used (e.g. poured into a wound). However,such electrosprayed beads may also contain other substances which arebeneficial for blood clotting and/or wound healing, since they can bemade from compositions that contain such substances, as described abovefor electrospun compositions. Electrosprayed beads can thus be used, forexample, for the release (e.g. slow release) of such beneficialcompounds at the site of a wound to which they are applied.

Compositions comprising clay minerals may be utilized to controlbleeding in a large variety of settings, which include but are notlimited to:

-   a) External bleeding from wounds (acute and chronic) through the use    of liquids, slurries, gels, sprays, foams, hydrogels, powder,    granules, or the coating of bandages with these preparations.-   b) Gastrointestinal bleeding through the use of an ingestible    liquid, slurry, gel, foam, granules, or powder.-   c) Epistaxis through the use of an aerosolized powder, sprays, foam,    patches, or coated tampon.-   d) Control of internal solid organ or boney injury through the use    of liquids, slurries, sprays, powder, foams, gels, granules, or    bandages coated with such.-   e) Promotion of hemostasis, fluid absorption and inhibition of    proteolytic enzymes to promote healing of all types of wound    including the control of pain from such wounds.

Many applications of the present invention are based on the knownproblems of getting the surfaces of bandages to conform to all surfacesof a bleeding wound. The use of granules, powders, gels, foams,slurries, pastes, and liquids allow the preparations of the invention tocover all surfaces no matter how irregular they are. For example, atraumatic wound to the groin is very difficult to control by simpledirect pressure or by the use of a simple flat bandage. However,treatment can be carried out by using a clay mineral in the form of, forexample, a powder, granule preparation, gel, foam, or very viscousliquid preparation that can be poured, squirted or pumped into thewound, followed by application of pressure. One advantage of thepreparations of the present invention is their ability to be applied toirregularly shaped wounds, and for sealing wound tracks, i.e. the pathof an injurious agent such as a bullet, knife blade, etc.

EXAMPLES Example 1

Electrospinning Gelatin, Bentonite and Super-Absorbent Polymer

To create a hemostatic bandage, gelatin (Sigma Aldrich #G-9391), as abasic structural element (carrier polymer) was utilized for itspotential to quickly dissolve in the wound (if desired and notcross-linked), promote some degree of coagulation, and act as a deliverysystem for bentonite, and/or quick absorb polymers. When electrospinninggelatin, a concentration of anywhere between 80 mg/mL to 300 mg/mL in2,2,2-trifluoroethanol (TFE) (Sigma Aldrich #T-8132) can be utilized.For this experiment, a larger gelatin concentration was desirablebecause it had the ability to hold/suspend particles that were added tothe solution. Both bentonite and super-absorbent polymer particles wereadded to the solution. ExquisiCat® Extra Strength SCOOP, premiumclumping cat litter, unscented, was utilized as the source of bentonite,and was added to the gelatin solution to increase liquid absorbency andcoagulation ability of the scaffold. For the bentonite, the pellets wereplaced in a mortar and pestle, and ground (pulverized) until smallerparticle-size pieces were achieved. By this process, no large piecesremained before adding it to the gelatin solution. Normally whenelectrospinning, a 18-guage needle is used, but for this experiment, a14-guage needle was necessary in order to allow the ground bentonite andsuper-absorbent polymer particles to pass through the needle tip.

The concentration of gelatin that was chosen for electrospinning rangedbetween 150 mg/mL to 250 mg/mL TFE. When constructing the electrospunbandages, 3 mL of solution was sufficient to obtain a sample, but 5 mLwas necessary when spinning onto a larger mandrel to create a fullbandage. FIG. 2 shows a scanning electron micrograph (SEM) ofelectrospun gelatin alone at a concentration of 200 mg/mL TFE.

The optimal concentration of ground bentonite to be put into the gelatinsolution was determined. Concentrations ranging from 100 mg/mL to 400mg/mL of ground bentonite were added to the gelatin solution todetermine the highest concentration possible that could be put into thegelatin without clogging the syringe or having all of the particles sinkto the bottom of the vial when pulling the solution into the syringe forelectrospinning. The highest concentration of pulverized bentonite thatallowed for successful electrospinning was 300 mg/mL in the gelatinsolution, and this concentration was utilized throughout.

The gelatin solution with suspended bentonite was spun at different flowrates, beginning at a slower rate of 4 mL/hr and increasing it to 45mL/hr. Going too fast would cause the solution to no longer spin andconstantly drip, but if the solution were spun slower the litterparticles would all sink to the bottom of the syringe. The optimal flowrate to spin the bentonite and gelatin was in the range of 5 to 10mL/hr. It was also spun at different distances between the syringeneedle and the mandrel, beginning at 9.5 inches away and then gettingcloser at 5 inches. The final distance of 6 inches was determined togive the best end result. FIG. 3 shows a SEM of gelatin with thepulverized bentonite.

The next step was testing the different super-absorbent polymers (blendsof crosslinked polyacrylic acid and their salts) for their absorbency.Each polymer was placed in 3 mLs of water and timed to determine howlong it took each polymer to form a gel. From these tests, the threepolymers that gelled the quickest were chosen for the experiment tocreate a “quick” absorb bandage. The three chosen, Norsocryl XFS(available from Arkema of Colombes, France), LiquiBlock 144, andNorsocryl s-35 (available from Arkema of Colombes, France), were basedon their particle distribution size (less than 200 microns, 300 microns,and 500 microns, and, respectively). These polymers were individuallyadded to gelatin samples and electrospun. A maximum of 100 mg/mL of thesuper-absorbent polymers remained suspended in the gelatin solution;therefore, this is the concentration that was utilized throughout theexperiment for all polymers. A solution of 200-250 mg/mL of gelatin inTFE and 100 mg/mL of polymer were added to the solution that was spun.This solution was spun without the addition of bentonite to determinehow much water the scaffolds would absorb during a 30-second exposure towater. After testing each electrospun polymer/gelatin scaffold, groundbentonite clay was then added to the solution and electrospun. The sameratios of each substance were maintained: 100 mg/mL of thesuper-absorbent polymer, 300 mg/mL of ground bentonite clay, and 250mg/ml of gelatin in TFE. The faster the rate each one was electrospun,the tougher and more cast-like the scaffold was; when the sample wasspun more slowly, the scaffold had more of a cotton-like appearance.Each sample was spun once at 4 mL/hr and then again at 10-15 mL/hr.

After each sample was collected, it was put through a hydration test todetermine the percentage of water it could absorb during a 30 secondexposure. The bandages were tested in both fixed (cross-linked) andun-fixed states. The cross-linking method utilized was a 30-minuteglutaraldehyde vapor fixation. For the cross-linking, smallbandage/fabric samples were placed in a 100 mm diameter Petri dishcontaining a 35 mm diameter Petri dish filled with 50% glutaaldehydesolution. Once the bandage sample was in place, the lid to the largerPetri dish was put into place to create an enclosed saturatedglutaraldehyde vapor environment for cross-linking. The fluid componentnever comes into direct contact with the bandage structure.

When spun at a higher flow rate (10 or 15 mL/hr) the polyacrylic acidwith a particle size distribution less than 300 microns produced ascaffold with a cast-like appearance, whereas when it was spun at aslower flow rate (4 mL/hr) it was more cotton-like, but was difficult toremove from the mandrel. A solution spun at 10 mL/hr with 300 mg/mL ofbentonite clay, 250 mg/mL gelatin in TFE, and 100 mg/mL of the samepolyacrylic acid had a 776% increase in weight when placed into waterfor 30 seconds, for an un-fixed scaffold, and a 1508% increase in weightfor the same scaffold in the cross-linked state. Further, this sampleretained its shape when exposed to water.

The sample utilizing the cross-linked polyacrylic acid (and its salt) ofless than 500 micron particle size (plus 250 mg/mL gelatin in TFE and300 mg/mL ground bentonite) had a cotton-like appearance regardless ofthe flow rate at which the sample was electrospun. The scaffold formedfrom this sample also absorbed more water in comparison to that formedwith the previous sample (polyacrylic acid with a particle sizedistribution less than 300 microns), showing a 1914% increase in weightwhen it was cross-linked. However, of the three polymers tested, thissample was also the most apt to dissolve when exposed to water. In fact,a sample could not be collected for measurement of water absorption whenit was in the un-fixed state due to complete dissolution.

The samples produced with a cross-linked polyacrylic acid (and its salt)of less than 200 micron particle size exhibited high increases in weightpercentage of 2623% for the fixed scaffold and 2114% for the un-fixedscaffold; however, the shape of this sample was not well retained uponexposure to water.

Due to its high level of water absorbency, coupled with excellent shaperetention, the super-absorbent polymer chosen for further investigationas an addition to the gelatin/bentonite clay solution was that made withcross-linked polyacrylic acid (and its salt) of less than 300 micronparticle size. FIG. 4 shows is a SEM of electrospun gelatin withpulverized bentonite clay and this superabsorbent polyacrylic acid.

The original bentonite utilized in these experiments was in the form ofcoarse pellets which were ground into fine pieces that were easilysuspended in the gelatin solution. Another material that is similar tothis, bentonite clay powder (Kalyx.com, Item #2194), was also utilized.Bentonite clay is available in powder size particles and was suspendedinto the gelatin solution much more efficiently because the particleswere so small. Therefore, the bentonite did not fall out of solutionwhen pulling it into the syringe or during electrospinning. When thisclay powder was used for electrospinning, the final scaffold generallyhad a soft, cottony texture, regardless of the electrospinning rate,though this need not always be the case. The clay powder and gelatinsolution was electrospun with and without the addition of the less than300 micron particle size cross-linked polyacrylic acid. The resultingscaffolds were tested both in a fixed and un-fixed form to determine theincrease in weight when placed in water for 30 seconds. When comparingthe scaffolds constructed with the coarse bentonite from cat litterverses the bentonite clay powder, the bentonite clay powder bandagesfell apart more easily when un-fixed, but when fixed this scaffoldabsorbed more water and retained its shape better than scaffoldsconstructed with pulverized coarse bentonite. FIGS. 5 and 6 show twoSEMs of bentonite clay powder, one with the less than 300 micronparticle size cross-linked polyacrylic acid (FIG. 5) and one without(FIG. 6).

Thus, one preferred bandage is electrospun from a composition made witha concentration of 200 mg of gelatin per mL of TFE, 300 mg of bentoniteclay powder per mL of the gelatin solution, and 100 mg of cross-linkedpolyacrylic acid (and its salts) of less than 300 micron particle size(LiquiBlock 144) per mL of the gelatin solution (FIG. 6). Thebandage/scaffold is fixed for a minimum of about 30 minutes with aglutaraldehyde vapor. This embodiment of the scaffold exhibited a 2413%increase in weight when placed in 3 mL of water for 30 seconds. Further,the scaffold did not lose its shape upon exposure to water.

Example 2

Coagulation Studies

Materials and Methods

Study materials for Parts I-IV were as follows: Part I: pulverizedbentonite or gelatin; Part II, electrospun fibroginogen, bentonite, orgelatin; Part III: pulverized bentonite, gelatin, and zeolite; and PartIV, pulverized bentonite and zeolite. Pulverized cat litter (as above inExample 1) was the source of bentonite. Gelatin was obtained from SigmaAldrich (catalog #G-9391). Zeolite (Quickclot) was obtained fromZ-Medica.

Determination of Platelet Function and Clot Structure Parameters Usingthe HAS™:

Hemodyne Hemostasis Analyzer (HAS™) provides a global evaluation of theintegrity of the coagulation system by reporting the parameters forceonset time (FOT), platelet contractile force (PCF), and clot elasticmodulus (CEM). In this instrument a small sample of whole blood istrapped between to parallel surfaces. Clotting is initiated by additionof a variety of clotting agents. During clot formation a downward forceis imposed from above and the degree of deformation is directly measuredby a displacement transducer. From this measurement, elastic modulus iscalculated. As the clot forms, the platelets within the clot attempt toshrink the clot in the process known as clot retraction. The forcesproduce pull on the movable upper plate and the subsequent deflection isdetected by the displacement transducer. The elastic modulus serves as acalibration constant for conversion of the displacement signal to force.A software package continually makes the calculations and plots clotelastic modulus (CEM—Kdynes per cm²) and platelet contractile force(PCF—Kdynes) as a function of time. CEM is a complex parameter that issensitive to changes in clot structure, fibrinogen concentration, therate of fibrin production and red cell flexibility. PCF is a thrombindependent function of platelets. It is sensitive to the rate of thrombinproduction, the presence of thrombin inhibitors, and the degree of GPIIb/IIIa exposure. The measurement is typically terminated at 20minutes.

All clots were formed using 700 μL of citrated whole blood. Clotting wasinitiated at time zero by adding CaCl₂ and increasing amounts of studymaterial (pulverized bentonite or gelatin). Final clotting conditionsincluded: CaCl₂ 10 mM, pH 7.4, ionic strength 0.15M and a final volumeof 0.750 mL. Final material concentrations in the blood samples were 0,10, 50 and 75 mg/mL. The force onset time (FOT) was determined from theinitial upswing in force and elastic modulus. Platelet function wassubsequently assessed as the force developed after 20 minutes ofmeasurement. Force (PCF) was recorded in kilodynes. Clot structure wasassessed by concurrently measuring the clot elastic modulus (CEM). CEMwas reported in kilodynes per cm².

Definition of HAS Parameters:

FOT is the speed at which thrombin is generated in whole blood. PCF isthe force produced by platelets during clot retraction and therefore ameasure of platelet function during clotting. CEM is measuredsimultaneously with PCF and it reflects the structural integrity of theclot. Very low PCF, low CEM, and prolonged FOT is associated withincreased bleeding risk. CEM is the best overall measure of clotintegrity and strength.

Determination of Thromboelastographic Parameters Using the TEG®:

The Thromboelastograph® Coagulation Analyzer 5000 (TEG®) measures theresponse to shearing of a formed clot; a pin, inserted into a rotatingcup containing whole blood moves with the cup as the fibrin polymerizes.The amount of movement of the pin is recorded as amplitude, whichreaches a maximum. The stronger the clot, the more the pin moves withthe cup and the higher the maximum amplitude (MA) or clot strength. Bothfibrin polymerization and platelet contraction contribute to the MA.

Assays were done as follows: Increasing amounts of study materialfollowed by 20 μL of 0.2M CaCl₂ and 340 μL of sodium citrated wholeblood were added to the sample cup. Final material concentrations in theblood samples were 0, 10, 50 and 75 mg/mL. Electrospun samples wereevaluated at 5 mg/mL. Clot formation was initiated.

Definition of Thromboelastograph Parameters:

The reaction time (R) is the time interval between the addition ofsample to the cup and the production of a signal of at least 2 mmamplitude. The R value is typically interpreted as the time required forinitial fibrin formation. The signal maximum amplitude (MA) is areflection of the maximum structural integrity obtained by the clot. Itis dependent on fibrin content, fibrin structure, platelet concentrationand platelet function. The shear elastic modulus strength (G) is acalculated parameter. G=5000MA/(100-MA). A thromboelastogram can beperformed which provides a visual inspection of this process.

Part I.

Study Description

The specific aims of this study were to 1) Determine if bentonite andgelatin are capable of altering blood clotting parameters and 2) Comparethe clotting capabilities of increasing concentrations of bentonite, andgelatin. The results are depicted in Table 1 and FIGS. 7A-C.

TABLE 1 Final Hemodyne HAS TEG Concentration FOT PCF CEM R MA G (mg/ml)(min) (Kdynes) (Kdynes/cm2) (min) (mm) (Dynes/sec) Bentonite 0 8 6.9022.64 7.8 57.5 6765 10 4 10.52 44.03 4.3 61.0 7821 50 2.5 13.44 50.103.8 62.0 8158 75 1 17.38 78.11 3.6 61.0 7821 Gelatin 0 8 6.90 22.64 7.857.5 6765 10 3 9.10 26.93 3.3 62.0 8158 50 3 13.23 42.72 3.3 59.0 719575 0 15.08 35.99 na na na na = Preclotted sample; unable to obtain validresults.

CONCLUSIONS

In this study, the interactions of bentonite and gelatin with wholeblood have been evaluated. The results indicate that both materialsproduce concentration dependent shortening of the onset of clottingaffecting the parameters of PCF and ECM. The TEG values of increasingconcentrations of bentonite are shown in FIG. 7C. The results alsodemonstrate that shortening of the onset of clotting leads to enhancedclot structural integrity.

Part II.

Study Description

The specific aims of this study were to 1) Determine if electrospunbentonite, gelatin and fibrinogen are capable of altering blood clottingparameters and 2) Compare the clotting capabilities of increasingconcentrations of bentonite, gelatin and fibrinogen. The results areshown in Table 2 and in FIGS. 8A-C.

TABLE 2 Final Hemodyne HAS TEG Conc. FOT PCF CEM R MA G (mg/ml) (min)(Kdynes) (Kdynes/cm²) (min) (mm) (Dynes/sec) Baseline 0 5.5 7.42 30.235.5 64.0 8889 Fibrinogen 90 ¹ 5 4.5 9.37 30.00 5.7 64.5 9085 Fibrinogen120 ² 5 3.5 9.69 31.56 4.3 67.5 10385 Fibrinogen 150 ³ 5 3.0 12.20 44.033.3 68.5 10873 Gelatin 200 ⁴ 5 3.0 7.74 43.09 3.9 64.0 8889 Gelatin200 + 5 5.0 8.34 49.64 3.5 64.0 8889 Bentonite 200 ⁵ Gelatin 200 + 103.0 10.40 70.50 2.5 66.0 9706 Bentonite 200 ⁵ ¹ Electrospun fibrinogenmat from a 90 mg/ml fibrinogen solution (Nano Letters, 3(2): 213-16,2003). ² Electrospun fibrinogen mat from a 120 mg/ml fibrinogen solution(Nano Letters, 3(2): 213-16, 2003). ³ Electrospun fibrinogen mat from a150 mg/ml fibrinogen solution (Nano Letters, 3(2): 213-16, 2003). ⁴Electrospun Gelatin mat from 200 mg/ml TFE. ⁵ Electrospun Gelatin matfrom 200 mg/ml TFE with 200 mg/ml bentonite added/in suspension.

CONCLUSIONS

-   1) Electrospun fibrinogen (5 mg/ml) shortened FOT and R and    increased PCF at all fibrinogen concentrations tested. CEM and MA    increased in the electrospun material with the highest fibrinogen    concentration (Fibrinogen 150).-   2) Gelatin 200 (5 mg/ml) shortened FOT and R, did not alter PCF or    MA and increased CEM.-   3) Gelatin 200+Bentonite 200 (5 mg/ml) had very little effect on FOT    and PCF and MA but increased CEM and shortened R.-   4) Gelatin 200+Bentonite 200 (10 mg/ml) shortened FOT and R and    increased PCF, CEM, and MA.

The overall results indicate that the combination of bentonite andgelatin have as good or better ability to initiate and form a strongclot as fibrinogen with the added advantage of being much less expensiveto produce. In addition, bentonite itself produces higher PCF and ECMvalues at lower concentrations than fibrinogen (also see Table 1). TheTEG (FIG. 8C) also demonstrates the favorable comparison of thegelatin/bentonite combination when compared to fibrogen.

Part III.

Study Description

The specific aims of this study were to 1) Determine if bentonite,gelatin and zeolite are capable of altering blood clotting parametersand 2) Compare the clotting capabilities of increasing concentrations ofbentonite, gelatin and zeolite. Results are given in FIGS. 9A and B (PCFand ECM), FIGS. 10A and B (PCF and ECM), and FIGS. 11A-E (TEG).

CONCLUSIONS

In this study, the interactions of bentonite, zeolite, and gelatin withwhole blood were evaluated. The results indicate that each one of thesematerials produces concentration dependent shortening of the onset ofclotting. The results also demonstrate that shortening of the onset ofclotting leads to enhanced clot structural integrity. Overall, theresults show that bentonite rapidly produces a clot that is as strong orstronger than that produced by zeolite, especially in terms of the CEMvalues. The low cost of bentonite and its flexibility (in terms of itsbeing made into many forms that are suitable for application to sites ofhemorrhage) are additional significant advantages.

Example 3

Use of Bentonite Composition to Stanch Bleeding In vivo

In an institutional review board approved study, two large swine (50-80kg) were used to test the ability of bentonite clay granules to stoparterial bleeding. These experiments were modeled after those of theU.S. Army Institute for Surgical Research in San Antonio, Tex. The modelis designed the test the ability of hemostatic agents to control highpressure arterial bleeding (see Acheson et al. Comparison of HemorrhageControl Agents Applied to Lethal Extremity Arterial Hemorrhage in Swine.J Trauma 2005:59; 865-875). After provision of proper anesthesia, thefirst animal underwent surgical exposure of the left and right femoralartery and the left carotid artery. A catheter was placed in the rightfemoral artery for arterial blood pressure monitoring. A 6 mmarteriotomy was created in the left femoral artery after lidocaine wasapplied to the area to prevent arterial spasm. The animal was allowed tohemorrhage for 30 seconds. At that time 3.5 ounces (approximately 100grams) of bentonite clay granules were poured into the wound (this isapproximately equivalent to the weight and volume of Quick Clot asrecommended by the manufacturer for use). Pressure was then applied withsimple gauze pad for 4 minutes. After this time pressure was released.No further bleeding was noted. The mean arterial blood pressure at thetime of application was 120 mmHg. The mean arterial blood pressure afterthe end of application did not change. Using the same animal anarteriotomy was made in the left carotid artery followed by immediateapplication of the 3.5 ounces of bentonite clay. Pressure was appliedfor 4 minutes. After this time pressure was released. No additionalhemorrhage was noted. The animal's blood pressure did not change.

The second animal underwent similar experimentation except that the leftcarotid artery was cannulated for monitoring of arterial blood pressure.Both the left and right femoral arteries were surgically isolated.Lidocaine was applied to the vessels to prevent vasospasm. A 6 mmarteriotomy was made in the right femoral artery. The animal was allowedto hemorrhage for 30 seconds. At this time 3.5 ounces of bentonite claywas applied and pressure was placed on the clay using simple medicalgauze for 4 minutes. At this time pressure was released and no furtherbleeding was observed. The mean arterial blood pressure at this time wasgreater than 80 mmHg. The experiment was repeated on the left femoralartery with the same results. Complete control of hemorrhage wasobtained after application of 3.5 ounces of bentonite clay followed by 4minutes of pressure. Mean arterial blood pressure was again greater than80 mmHg. All animals were humanely euthanized after the experiment. Theabove described testing is in some regards more rigorous than the modelcreated by the U.S. Army in that the mean arterial blood pressures atthe time of application were generally higher which provides a furtherchallenge in controlling hemorrhage due to the hydrostatic forces withinthe arterial vasculature which would tend to disrupt a formed clot afterpressure is released from the wound. It was noted in all cases that ahard cast was formed in the wound cavity. This is due to the highlyabsorptive nature of the bentonite clay. In the second animal, thesecasts were easily removed from the wound allowing for completevisualization of the femoral arteries. Neither artery had beentransected. Removal of the clay and clot directly over the vesselpromoted rebleeding demonstrating that the vessel was not irreparablydamaged. The ability to remove the cast should have medical and surgicaladvantages at the time of vascular repair.

In the paper published by Acheson and colleagues (Acheson et al.Comparison of Hemorrhage Control Agents Applied to Lethal ExtremityArterial Hemorrhage in Swine. J Trauma 2005:59; 865-875) all dressingsand hemostatic strategies tested failed to prevent death, except thefibrin sealant dressing which allowed for a 66% survival rate. The useof the Hemcon Bandage, Army Field Dressing, and Quick Clot did notproduce any survivors in the experiment. Using a different model ofhemostasis Alam and colleagues (Alam, et al. J Trauma 2003;54:1077-1082) demonstrated the superiority of Quick Clot when comparedto the Hemocon Bandage, the Rapid Deployment Hemostat Dressing, TraumaDex, and a standard field dressing. This model however is one ofcomplete transection of the femoral artery and vein, and animals areallowed to hemorrhage for 5 minutes. At this time arterial bloodpressure is very low. Also, after application of the hemostaticstrategy, pressure is applied to the wound for 5 minutes. Therefore,this model is not as severe as the previously described Army model. Thisis further evidenced by the fact that Quick Clot produced no survivorsin the Army study. In another study Alam et al (J Trauma 2004;56:974-983) using his previoius model described above, variations ofQuickclot were compared against the Hemocon bandage, Trauma Dex, FastAct (bovine clotting factor), and Quick Relief (a superabsorbent polymerwith potassium salt). The variations of Quickclot were partiallyhydrated in an attempt to reduce the thermogenic reaction produced byQuickclot. In this study only the original Quick Clot product preventedany mortality. All other products produce mortality rates ranging from28% to 83%. This data indicates that the thermogenic reaction of QuickClot is likely to be most responsible for its hemostatic actions.

The combined data from the above studies would indicate that thebentonite clay strategy described in this application may provide asuperior method of hemostasis especially when cost of production,storage, and form variation (granules, bandage, etc) are taken intoaccount.

While the invention has been described in terms of its preferredembodiments, those skilled in the art will recognize that the inventioncan be practiced with modification within the spirit and scope of theappended claims. Accordingly, the present invention should not belimited to the embodiments as described above, but should furtherinclude all modifications and equivalents thereof within the spirit andscope of the description provided herein.

We claim:
 1. A method of stanching blood flow in a hemorrhaging woundhaving a high-pressure blood flow, comprising without causing anexothermic reaction, applying a composition comprising kaolin to saidhemorrhaging wound having high-pressure bleeding in a quantitysufficient to promote hemostasis and said kaolin promoting bloodclotting and stanching of high-pressure blood flow from the wound untilthe applied kaolin stanches the high-pressure blood flow.
 2. The methodof claim 1, wherein said kaolin is in a form selected from the groupconsisting of granules, powder, liquid, paste, gel, micron beads,impregnated in a bandage, and electrospun into a bandage.
 3. The methodof claim 1, wherein said hemorrhaging wound is an external wound.
 4. Themethod of claim 1, wherein said hemorrhaging wound is an internal wound.5. The method of claim 1, wherein said step of applying is performed byplacement of a substrate which carries said composition on or in saidhemorrhaging wound.
 6. The method of claim 1, further includingformation of a cast comprising the kaolin and blood from saidhemorrhaging wound.
 7. The method of claim 1, including applyingpressure with a gauze pad or placing pressure on the kaolin using gauze.8. The method of claim 1, wherein the applying step is performed withouttissue damage by burning.
 9. The method of claim 1, wherein the wound isan irregularly shaped wound.
 10. The method of claim 1, wherein thewound has high-pressure arterial bleeding.
 11. A method of stanchingblood flow in a hemorrhaging wound having a high-pressure blood flow,comprising applying to said wound a composition comprising kaolin and/orbentonite, in a quantity sufficient to stanch the high-pressure bloodflow, and said kaolin and/or bentonite is applied until it stanches thehigh-pressure blood flow from the wound.
 12. A method of stanching ahigh-pressure blood flow, comprising: applying kaolin to thehigh-pressure blood flow, until the applied kaolin stanches thehigh-pressure blood flow.
 13. The method of claim 12, in which thehigh-pressure blood flow is stanched without an exothermic reaction. 14.The method of claim 12, wherein said kaolin is in a form selected fromthe group consisting of granules, liquid, gel, micron beads,incorporated into a fiber-like material, a mortar, a foam, a viscousliquid, and a semisolid-semiliquid.
 15. The method of claim 12, whereinsaid kaolin is in a powder.
 16. The method of claim 12, wherein saidkaolin is in a paste.
 17. The method of claim 12, wherein said kaolin isimpregnated in a bandage.
 18. The method of claim 12, wherein saidkaolin is electrospun into a bandage.
 19. The method of claim 12,wherein said step of applying is performed by placement of a gauzesubstrate carrying said kaolin on and/or in a bleeding wound, whereinsaid substrate conforms to the shape of said wound.
 20. The method ofclaim 12, further comprising the step of simultaneously or sequentiallyapplying to the high-pressure blood flow one or more substances selectedfrom the group consisting of chitosan, fibrin, superabsorbent polymers,polyethylene glycol, vasoactive catecholamines, vasoactive peptides,antimicrobial agents, a quick absorb polymer, and anesthetic agents. 21.The method of claim 12, further comprising simultaneously orsequentially applying fibrinogen to the high-pressure blood flow. 22.The method of claim 12, further comprising simultaneously orsequentially applying thrombin to the high-pressure blood flow.
 23. Themethod of claim 12, further comprising simultaneously or sequentiallyapplying calcium to the high-pressure blood flow.
 24. The method ofclaim 12, further comprising simultaneously or sequentially applyingdextran to the high-pressure blood flow.
 25. The method of claim 12,further comprising simultaneously or sequentially applying one or morecellulose types to the high-pressure blood flow.
 26. The method of claim12, wherein said high-pressure blood flow is from an irregularly shapedwound.
 27. The method of claim 12, wherein said high-pressure blood flowis from a bullet wound.
 28. The method of claim 12, wherein saidhigh-pressure blood flow is from arterial bleeding.
 29. The method ofclaim 12, wherein said high-pressure blood flow is from an externalwound.
 30. The method of claim 12, wherein said high-pressure blood flowis from a location of intentional trauma.
 31. The method of claim 30,wherein said intentional trauma is from a medical procedure.
 32. Themethod of claim 12, wherein said high-pressure blood flow is from aninternal wound.
 33. The method of claim 12, wherein the method comprisesapplying said kaolin to a site of internal bleeding.
 34. The method ofclaim 33, wherein said site of internal bleeding is a location ofintentional trauma, wherein said intentional trauma is from a medicalprocedure.
 35. The method of claim 32, wherein said step of applying isperformed by placement of a substrate which carries said kaolin onand/or in said internal wound.
 36. The method of claim 12, wherein theapplying step is performed without tissue damage by burning.
 37. Themethod of claim 12, wherein said high-pressure blood flow is from anorgan.
 38. The method of claim 11, wherein said step of applying isperformed by placement of a substrate which carries said composition onand/or in said wound and wherein said substrate conforms to the shape ofsaid wound.
 39. The method of claim 38, wherein said substrate is agauze substrate.
 40. The method of claim 11, wherein said kaolin and/orbentonite is in a form selected from the group consisting of granules,liquid, gel, micron beads, incorporated into a fiber-like material, amortar, a foam, a viscous liquid, a powder, a paste, electrospun into abandage, and a semisolid-semiliquid.
 41. The method of claim 11, whereinsaid kaolin and/or bentonite is impregnated in a bandage.
 42. The methodof claim 11, further comprising simultaneously or sequentially applyingfibrinogen to said wound.
 43. The method of claim 11, further comprisingsimultaneously or sequentially applying thrombin to said wound.
 44. Themethod of claim 11, further comprising simultaneously or sequentiallyapplying dextran to said wound.
 45. The method of claim 11, furthercomprising simultaneously or sequentially applying one or more cellulosetypes to said wound.
 46. The method of claim 1, further comprisingsimultaneously or sequentially applying one or more substances selectedfrom the group consisting of fibrinogen, thrombin, or dextran to saidwound.
 47. A method of stanching blood flow in a hemorrhaging woundhaving a high-pressure blood flow, comprising applying to said wound acomposition comprising one or more clay minerals, in a quantitysufficient to stanch the high-pressure blood flow, and said one or moreclay minerals is applied until it stanches the high-pressure blood flowfrom the wound.
 48. The method of claim 47, wherein said one or moreclay minerals is in a powder.
 49. The method of claim 47, wherein theone or more clay minerals is in a form selected from the groupconsisting of a liquid, a gel, and a paste.
 50. The method of claim 47,wherein said one or more clay minerals is impregnated in a bandage. 51.The method of claim 47, wherein said step of applying is performed byplacement of a gauze substrate carrying said one or more clay mineralson and/or in a bleeding wound, wherein said substrate conforms to theshape of said wound.
 52. A bandage for providing hemostasis in ahemorrhaging wound having a high-pressure blood flow, comprising: asubstrate; a composition including one or more clay minerals with saidsubstrate, wherein said one or more clay minerals is positioned withrespect to said substrate so as to contact a hemorrhaging wound whensaid bandage is applied to said hemorrhaging wound, wherein said one ormore clay minerals is present in a quantity sufficient to promote bloodclotting and hemostasis and to stanch high pressure blood flow from thehemorrhaging wound, and wherein said composition does not includeingredients which cause an exothermic reaction when in contact withblood.
 53. The bandage of claim 52, wherein said substrate is gauze. 54.The bandage of claim 52, wherein said substrate is a flexible spongematerial.
 55. The bandage of claim 52, wherein said one or more clayminerals is in a form selected from the group consisting of granules,liquid, gel, and micron beads.
 56. The bandage of claim 52, furthercomprising one or more substances selected from the group consisting ofchitosan, fibrin, superabsorbent polymers, polyethylene glycol,vasoactive catecholamines, vasoactive peptides, antimicrobial agents,and anesthetic agents.
 57. The bandage of claim 52, further comprising aflexible substrate that is affixed to a body part remote from saidhemorrhaging wound.
 58. The bandage of claim 52, wherein said one ormore clay minerals is in a form selected from the group consisting amortar, a foam, a viscous liquid, incorporated into a fiber material,and a semisolid-semiliquid.
 59. The bandage of claim 52, wherein saidone or more clay minerals is a powder.
 60. The bandage of claim 52,wherein said one or more clay minerals is in a paste.
 61. The bandage ofclaim 52, wherein said one or more clay mineral is impregnated in thebandage.
 62. The bandage of claim 52, wherein said substrate isconfigured to conform to the shape of said wound.
 63. The bandage ofclaim 52, wherein said bandage is configured for use in treating abullet wound or a knife wound.
 64. A device for providing hemostasis ina hemorrhaging wound having a high-pressure blood flow, comprising: asubstrate; a composition including one or more clay minerals on or insaid substrate, wherein said one or more clay minerals is positionedwith respect to said substrate so as to contact a hemorrhaging woundwhen said substrate is applied to said hemorrhaging wound, wherein saidone or more clay minerals is present in a quantity sufficient to promoteblood clotting and hemostasis and to stanch high pressure blood flowfrom the hemorrhaging wound, and wherein said one or more clay mineralsdoes not cause an exothermic reaction when in contact with blood.
 65. Amethod of stanching blood flow in a hemorrhaging wound having ahigh-pressure blood flow, comprising applying to said wound acomposition comprising an aluminum silicate, in a quantity sufficient tostanch the high-pressure blood flow, and said aluminum silicate isapplied until it stanches the high-pressure blood flow from the wound;wherein the aluminum silicate is not a zeolite.
 66. The method of claim65, wherein said aluminum silicate is a clay mineral.
 67. The method ofclaim 65, wherein said aluminum silicate is a powder.
 68. The method ofclaim 65, wherein the aluminum silicate is in a form selected from thegroup consisting of a liquid, a gel, and a paste.
 69. The method ofclaim 65, wherein said aluminum silicate is impregnated in a bandage.70. The method of claim 65, wherein said step of applying is performedby placement of a gauze substrate carrying said aluminum silicate onand/or in a bleeding wound, wherein said substrate conforms to the shapeof said wound.
 71. A bandage for providing hemostasis in a hemorrhagingwound having a high-pressure blood flow, comprising: a substrate; acomposition including an aluminum silicate with said substrate, whereinsaid aluminum silicate is positioned with respect to said substrate soas to contact a hemorrhaging wound when said bandage is applied to saidhemorrhaging wound, wherein said aluminum silicate is present in aquantity sufficient to promote blood clotting and hemostasis and tostanch high pressure blood flow from the hemorrhaging wound, and whereinthe aluminum silicate is not a zeolite.
 72. The bandage of claim 71,wherein said aluminum silicate is a clay mineral.
 73. The bandage ofclaim 71, wherein said substrate is gauze.
 74. The bandage of claim 71,wherein said substrate is a flexible sponge material.
 75. The bandage ofclaim 71, wherein said aluminum silicate is in a form selected from thegroup consisting of granules, liquid, gel, and micron beads.
 76. Thebandage of claim 71, further comprising one or more substances selectedfrom the group consisting of chitosan, fibrin, superabsorbent polymers,polyethylene glycol, vasoactive catecholamines, vasoactive peptides,antimicrobial agents, and anesthetic agents.
 77. The bandage of claim71, further comprising a flexible substrate that is affixed to a bodypart remote from said hemorrhaging wound.
 78. The bandage of claim 71,wherein said aluminum silicate is in a form selected from the groupconsisting a mortar, a foam, a viscous liquid, incorporated into a fibermaterial, and a semisolid-semiliquid.
 79. The bandage of claim 71,wherein said aluminum silicate is a powder.
 80. The bandage of claim 71,wherein said aluminum silicate is in a paste.
 81. The bandage of claim71, wherein said aluminum silicate is impregnated in the bandage. 82.The bandage of claim 71, wherein said substrate is configured to conformto the shape of said wound.
 83. The bandage of claim 71, wherein saidbandage is configured for use in treating a bullet wound or a knifewound.
 84. A device for providing hemostasis in a hemorrhaging woundhaving a high-pressure blood flow, comprising: a substrate; acomposition including an aluminum silicate on or in said substrate,wherein said aluminum silicate is positioned with respect to saidsubstrate so as to contact a hemorrhaging wound when said substrate isapplied to said hemorrhaging wound, wherein said aluminum silicate ispresent in a quantity sufficient to promote blood clotting andhemostasis and to stanch high pressure blood flow from the hemorrhagingwound, and wherein the aluminum silicate is not a zeolite.
 85. Thebandage of claim 84, wherein said aluminum silicate is a clay mineral.